Field
The present invention relates to methods for making isoquinoline compounds and the intermediate compounds achieved thereby.
State of the Art
Isoquinoline compounds are known to be effective in the treatment and prevention of conditions and disorders associated with HIF, including anemia and tissue damage caused by ischemia and/or hypoxia (see, e.g., Robinson et al. (2008) Gastroenterology 134(1): 145-155; Rosenberger et al. (2008) Nephrol Dial Transplant 23(11):3472-3478). Specifically, the compounds and methods disclosed herein can be used as, or in the preparation of, isoquinoline compounds for inhibiting HIF hydroxylase activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF), which can then be used to treat and prevent HIF-associated conditions and disorders.
To date, a number of synthetic routes for the preparation of substituted isoquinoline compounds have been published. In 1966, Caswell et al. (Heterocyclyl Chem 1966, (3), 328-332) reported the synthesis of 4-hydroxy-3-carbomethoxy-1(2H)-isoquinoline, and the 6- and 8-methoxy substituted derivatives thereof, via the Gabriel-Coleman rearrangement of phthalimidoacetate with sodium in methanol, preferably at high temperatures (105° C.) in a sealed reaction vessel. Whereas such methods did provide an excess of one regioisomer, the substitution was dictated by the electronic nature of the substituent, not the desire of the chemist.
In 1978, Suzuki et al. (Synthesis 1978 (6), 461-462) reported the synthesis of 4-hydroxy-3-carbomethoxy-1(2H)-isoquinoline via the acid catalyzed ring opening and subsequent intramolecular cyclization of 4-methoxycarbonyl-1,3-oxazole, which was prepared from phthalic anhydride and methyl isocyanoacetate. Suzuki et al. also reported the synthesis of the nitro substituted 4-hydroxy-3-carbomethoxy-1(2H)-isoquinoline, however, the methods disclosed therein provided a mixture of the 6- and 7-nitro isoquinoline compounds.
Weidmann et al. (U.S. Pat. No. 6,093,730) reported the synthesis of various substituted isoquinoline-3-carboxamides via chromatographic separation of the 4-hydroxy-3-carbomethoxy-1(2H)-isoquinoline isomers provided by the Caswell et al. synthesis, followed by hydrolysis of the methyl ester, activation of the corresponding acid to the acid halide, and condensation with glycine methyl ester.
Other methods for the preparation of substituted isoquinoline compounds have been reported in U.S. Pat. No. 7,629,357 and U.S. Pat. No. 7,928,120. U.S. Pat. No. 7,928,120 teaches the preparation of substituted cyanoisoquinoline compounds from an optionally substituted 2-methylbenzoic acid ester via reaction with a halogenating reagent to provide the corresponding 2-(halomethyl)benzoic acid ester, followed by reaction with a N-protected glycine ester, and finally cyclization/aromatization using a base and optionally an oxidizing agent. Such methods have an advantage over the documents described hereinabove in that the disclosed process affords only a single isomer of the 5-, 6-, 7-, or 8-substituted isoquinoline compounds. However, only halo and cyano substituents at the 1-position of the isoquinoline are provided. U.S. Pat. No. 7,629,357 discloses methods for the synthesis of various substituents at the 1-position of variously substituted isoquinoline compounds, including 1-methyl isoquinoline compounds. The 1-methyl isoquinoline compounds of U.S. Pat. No. 7,629,357 are prepared by first reacting the corresponding 1,4-dihydroxyisoquinoline compound with phosphorous oxychloride or phosphorous oxybromide to afford the 1-chloro or 1-bromoisoquinoline compound, followed by methylation using either trimethylboroxine with tetrakis(triphenylphosphine)palladium or an excess of n-butyllithium followed by methyliodide.